Silence Therapeutics’ Divesiran Hits Phase II Goal, Sets Up Phase III PV Trial

Key Points

• Divesiran met the Phase II SANRECO primary endpoint in phlebotomy-dependent polycythemia vera, with 88% of treated patients maintaining hematocrit below 45% without phlebotomy versus 18% on placebo.
• The treatment substantially reduced phlebotomy needs: more than 90% of divesiran patients required none through week 36, compared with 12.5% of placebo patients. It also improved hematocrit control, iron-metabolism markers and quality-of-life measures.
• Silence reported no new safety concerns and plans to seek FDA guidance by year-end before launching a Phase III trial in the first half of 2027, likely testing a quarterly dosing schedule.

Silence Therapeutics NASDAQ: SLN reported top-line results from its Phase II SANRECO trial of divesiran in patients with phlebotomy-dependent polycythemia vera, or PV, with the study meeting its primary endpoint and supporting the company’s plan to advance a quarterly dosing regimen into Phase III.

PV is a rare myeloproliferative neoplasm in which elevated hematocrit levels can increase health risks. According to Chief R&D Officer Steven Romano, treatment is intended to keep hematocrit below 45%, often through therapeutic phlebotomy. SANRECO enrolled 48 patients who met World Health Organization criteria for PV and were considered phlebotomy-dependent, defined as having received at least three phlebotomies in the prior six months or five in the prior year.

Primary Endpoint Results

The randomized, double-blind Phase II portion of SANRECO evaluated divesiran at 6 mg/kg administered every six weeks or every 12 weeks, compared with placebo. The primary endpoint was the proportion of patients maintaining hematocrit below 45% without requiring phlebotomy during weeks 18 through 36.

Romano said 88% of patients receiving divesiran across the combined active-treatment arms met the response criteria, compared with 18% of patients receiving placebo. The company reported a placebo-adjusted difference of nearly 70 percentage points and a p-value of less than 0.0001.

Both dosing schedules showed high response rates. The every-12-week arm had a response rate above 80%, while the every-six-week arm exceeded 90%, according to Romano. Although the study was powered to compare the combined active arms with placebo rather than each individual dosing arm with placebo, he said both schedules appeared to have “relatively similar” effects in the smaller individual groups.

A sensitivity analysis involving 40 patients who met the same phlebotomy-dependence criteria used in the company’s earlier Phase I study produced a divesiran response rate of nearly 90%, Romano said.

Phlebotomy and Secondary Measures

The mean number of phlebotomies from week zero through week 36 was 0.2 among patients in the combined divesiran arms, compared with 2.1 among placebo patients. More than 90% of divesiran-treated patients did not require any phlebotomies during that period, versus 12.5% of placebo-treated patients.

Silence also said divesiran-treated groups showed improvements in secondary measures including hematocrit control, markers of iron metabolism such as ferritin, and patient-reported quality-of-life outcomes. The company plans to present more detailed data at future scientific meetings, including the American Society of Hematology meeting in New Orleans in December.

On symptom data, Romano said results from quality-of-life instruments, including measures focused on fatigue, were moving “in the right direction.” He said the company expects to use the Phase II findings to inform assumptions for a potentially more robustly powered symptom assessment in Phase III.

Safety Profile and Phase III Planning

Romano said divesiran was generally well tolerated, with no new safety issues identified. Injection-site reactions were described as infrequent, grade 1 and self-limiting. The company reported two investigator-reported anemia adverse events, both grade 1 and not symptomatic; both occurred in the every-six-week arm.

The company also observed a modest increase in platelet counts, which Romano said was expected for a hepcidin-directed therapy that restricts iron availability to bone marrow. He said there was no change in white blood cell counts and that the safety observations were consistent with the company’s Phase I findings.

Silence plans to seek an end-of-Phase II meeting with the U.S. Food and Drug Administration by year-end and expects to begin a Phase III registration trial in the first half of 2027. Romano said the company intends to advance the less frequent every-12-week, or quarterly, dosing interval.

While final Phase III details have not been established, Romano said the company expects a parallel-group, one-to-one randomized design and anticipates discussions with the FDA regarding efficacy requirements and the size of the safety database. He said a trial could potentially involve roughly 200 to 250 patients and require an estimated 12 to 18 months for enrollment, though those details remain subject to regulatory discussions.

Chairman and Interim Principal Executive Officer Iain Ross said the company sees divesiran as a potential treatment for patients requiring phlebotomy regardless of whether they are also receiving stable cytoreductive therapy. He said Silence believes the data support a differentiated profile combining hematocrit control, reduced phlebotomy burden and infrequent dosing.

About Silence Therapeutics (NASDAQ:SLN)

Silence Therapeutics plc is a clinical-stage biotechnology company focused on the discovery and development of ribonucleic acid interference (RNAi) therapeutics. Leveraging its proprietary EnCore lipid nanoparticle delivery platform, the company aims to silence disease-causing genes in the liver and other tissues. Silence's technology is designed to enhance targeted delivery of small interfering RNA (siRNA) molecules, with the goal of achieving durable therapeutic effects and improved safety profiles compared with traditional drug modalities.

The company's lead product candidates include SLN360, an siRNA therapeutic designed to reduce lipoprotein(a) levels for cardiovascular risk reduction, and SLN124, aimed at treating hereditary hemochromatosis and beta-thalassemia by modulating iron metabolism.

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